Effects of Computer-Assisted Social Skills Training in Children With Disruptive Behavior Disorders: A Randomized Controlled Trial.

OBJECTIVE: Computer-assisted child-focused interventions are expected to improve efficiency and personalization of therapist-led treatments for children and adolescents. However, therapist-led, outpatient interventions using computer assistance are lacking for children with oppositional defiant disorder (ODD) or conduct disorder (CD). The present randomized controlled trial examined the efficacy of individualized computer-assisted social skills training for children with aggressive behavior compared to a resource activation intervention. METHOD: A total of 100 children aged 6-12 years with a diagnosis of ODD/CD and peer-related aggression were randomly (1:1) assigned to either individually delivered computer-assisted social skills training (ScouT) or an individually delivered supportive resource activation treatment (STARK). The primary outcome was parent-rated peer-related aggression, assessed with the respective scale of the Questionnaire for Aggressive Behavior of Children (FAVK) and measured at pre-assessment and after the 16-week intervention (post-assessment). Further parent-, self-, teacher- and/or clinician-rated outcomes included ODD and CD symptoms, a wide range of behavioral and emotional symptoms, callous-unemotional traits, functional impairment, and quality of life. RESULTS: After correcting for multiple testing, analyses of covariance comparing the efficacy of ScouT to the efficacy of STARK yielded small to moderate treatment effects in favor of the ScouT condition regarding parent-rated peer-related aggression (primary outcome; d = -0.64, 95% CI = -1.05, -0.24), parent-rated callous and uncaring traits, and parent-rated quality of life. However, the analyses did not reveal any significant effects for self- or teacher-rated peer-related aggression assessed with the respective scale of the FAVK (self-report: d = -0.21, 95% CI = -0.69, 0.29; teacher rating: d = -0.17, 95% CI = -0.56, 0.22). Moreover, after controlling for multiple comparisons, no significant effects emerged for the following: parent-, self-, and teacher-rated adult-related aggression; parent-, self-, teacher-, and clinician-rated ODD and CD symptoms; parent-, self-, and teacher-rated emotional and behavioral symptoms; and parent-rated functional impairment. CONCLUSION: According to parent ratings, school-age children with disruptive behavior disorders and peer-related aggression seem to benefit more from individualized, computer-assisted social skills training than from resource activation treatment. However, this conclusion is limited by the missing effects on the clinician-, self-, and teacher-rated measures. CLINICAL TRIAL REGISTRATION INFORMATION: Treatment of Children With Peer Related Aggressive Behavior (ScouT); https://clinicaltrials.gov/; NCT02143427.

Efficacy of an Individualized Computer-Assisted Social Competence Training Program for Children With Oppositional Defiant Disorders/Conduct Disorders.

Group-based child-centered cognitive behavioral therapy (CBT) for children with aggressive behavior has been found to significantly reduce child behavior problems. Nevertheless, most children suffer from residual symptoms at the end of treatment. Therefore, individualized interventions that treat the specific problem-maintaining factors and that use digital support may enhance treatment effects. However, enhanced computer-facilitated interventions have not been examined in clinical samples. Therefore, we tested the efficacy of an individualized computer-facilitated social skills training for children with clinically referred aggressive behavior problems. Fifty children aged 6-12 years with peer-related aggressive behavior problems were included in a within-subject design with two phases (waiting, treatment). The course of the outcome measures during an 8-week waiting phase was compared with that in the subsequent treatment phase (16 weekly child sessions and 2 parent psychoeducation contacts at the beginning of the treatment) using multilevel modeling. The primary outcome was peer-related aggressive behavior rated by parents. Further outcome measures included parent ratings and patient self-reports of aggressive and prosocial behavior. No significant changes occurred for any of the outcome variables during the waiting phase. During treatment, most parent-rated outcome measures (including the primary outcome measure) showed a significant decrease, which was stronger than changes in the waiting phase. Most self-rated outcome measures also showed significant decreases during treatment, but a stronger decrease than in the waiting phase was only found for peer-related aggressive behavior. The computer-facilitated social skills training appears to be an effective CBT intervention for children with peer-related aggressive behavior.

Both lethal and edema toxins of Bacillus anthracis disrupt the human dendritic cell chemokine network.

Bacillus anthracis, the agent of anthrax, produces two main virulence factors: a capsule and two toxins. Both lethal toxin (LT) and edema toxin (ET) paralyze the immune defense system. Here, we analyze the effects of LT and ET on the capacity of human monocyte-derived dendritic cells (MoDC) to produce proinflammatory chemokines. We show that both toxins disrupt proinflammatory chemokine production. LT has more pronounced effects than ET on CXCL8 production, which is correlated with impaired recruitment of neutrophils in vitro. Finally, we show that both toxins also differentially disrupt IL-12p70, IL-10, and TNF-α production. Taken together, these results demonstrate that both B. anthracis toxins alter MoDC functions and the activation of the innate immune system.

Shape-based tracking allows functional discrimination of two immune cell subsets expressing the same fluorescent tag in mouse lung explant.

Dendritic Cells (DC) represent a key lung immune cell population, which play a critical role in the antigen presenting process and initiation of the adaptive immune response. The study of DCs has largely benefited from the joint development of fluorescence microscopy and knock-in technology, leading to several mouse strains with constitutively labeled DC subsets. However, in the lung most transgenic mice do express fluorescent protein not only in DCs, but also in closely related cell lineages such as monocytes and macrophages. As an example, in the lungs of CX(3)CR1(+/gfp) mice the green fluorescent protein is expressed mostly by both CD11b conventional DCs and resident monocytes. Despite this non-specific staining, we show that a shape criterion can discriminate these two particular subsets. Implemented in a cell tracking code, this quantified criterion allows us to analyze the specific behavior of DCs under inflammatory conditions mediated by lipopolysaccharide on lung explants. Compared to monocytes, we show that DCs move slower and are more confined, while both populations do not have any chemotactism-associated movement. We could generalize from these results that DCs can be automatically discriminated from other round-shaped cells expressing the same fluorescent protein in various lung inflammation models.

Differential role of the interleukin-17 axis and neutrophils in resolution of inhalational anthrax.

The roles of interleukin-17 (IL-17) and neutrophils in the lung have been described as those of two intricate but independent players. Here we identify neutrophils as the primary IL-17-secreting subset of cells in a model of inhalation anthrax using A/J and C57BL/6 mice. With IL-17 receptor A knockout (IL-17RA-/-) mice, we confirmed that IL-17A/F signaling is instrumental in the self-recruitment of this population. We also show that the IL-17A/F axis is critical for surviving pulmonary infection, as IL-17RA-/- mice become susceptible to intranasal infection by Bacillus anthracis Sterne spores. Strikingly, infection with a fully virulent strain did not affect IL-17RA-/- mouse survival. Eventually, by depleting neutrophils in wild-type and IL-17RA-/- mice, we demonstrated the crucial role of IL-17-secreting neutrophils in mouse survival of infection by fully virulent B. anthracis. This work demonstrates the important roles of both IL-17 signaling and neutrophils in clearing this pathogen and surviving pulmonary B. anthracis infection.

Anthrax toxins: a weapon to systematically dismantle the host immune defenses.

Successful colonization of the host by bacterial pathogens relies on their capacity to evade the complex and powerful defenses opposed by the host immune system, at least in the initial phases of infection. The two toxins of Bacillus anthracis, lethal toxin and edema toxin, appear to have been shaped by evolution to assist the microorganism in this crucial function, in addition to act as general toxins acting on almost all cell types. Edema toxin causes a consistent elevation of cAMP, an important second messenger the production of which is normally strictly controlled in mammalian cells, whereas lethal toxin cleaves most isoforms of mitogen-activated protein kinase kinases. By disrupting or subverting central modules common to all the principal signaling networks which control immune cell activation, effector function and migration, the anthrax toxins effectively and systematically dismantle both the innate and the adaptive immune defenses of the host. Here, we review the specific effects of the lethal and edema toxins of B. anthracis on the activation and function of phagocytes, dendritic cells and lymphocytes. We also discuss some open issues which should be addressed to gain a comprehensive insight into the complex relationship that B. anthracis establishes with the host.

Anthrax, toxins and vaccines: a 125-year journey targeting Bacillus anthracis.

Bacillus anthracis is the causative agent of anthrax, a disease that plagues both humans and various animal species. Effective vaccines are available, but those approved for human use are crude culture supernatants that require multiple injections and a yearly boost. Many experts agree that it is now time for the next generation of human vaccines against anthrax. Accordingly, this review will succinctly focus upon: pathogenesis of B. anthracis, with particular emphasis upon the immune system; the pertinent biophysical nature of protective antigen, which includes how the protein toxin component affords protection as a vaccine target; alternative methods for improving protective antigen as an immunogen; and additional B. anthracis antigens that might further sustain protective titers in humans. In addition to a better understanding of the disease process elicited by B. anthracis, which will logically lead to better vaccines (and therapeutics), there also needs to be the same level of open-mindedness applied to the politics of anthrax.

Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route.

Inhalational anthrax is a life-threatening infectious disease of considerable concern, especially because anthrax is an emerging bioterrorism agent. The exact mechanisms leading to a severe clinical form through the inhalational route are still unclear, particularly how immobile spores are captured in the alveoli and transported to the lymph nodes in the early steps of infection. We investigated the roles of alveolar macrophages and lung dendritic cells (LDC) in spore migration. We demonstrate that alveolar macrophages are the first cells to phagocytose alveolar spores, and do so within 10 min. However, interstitial LDCs capture spores present in the alveoli within 30 min without crossing the epithelial barrier suggesting a specific mechanism for rapid alveolus sampling by transepithelial extension. We show that interstitial LDCs constitute the cell population that transports spores into the thoracic lymph nodes from within 30 min to 72 h after intranasal infection. Our results demonstrate that LDCs are central to spore transport immediately after infection. The rapid kinetics of pathogen transport may contribute to the clinical features of inhalational anthrax.

Contribution of toxins to the pathogenesis of inhalational anthrax.

Inhalational anthrax is a life-threatening infectious disease of considerable concern, especially as a potential bioterrorism agent. Progress is gradually being made towards understanding the mechanisms used by Bacillus anthracis to escape the immune system and to induce severe septicaemia associated with toxaemia and leading to death. Recent advances in fundamental research have revealed previously unsuspected roles for toxins in various cell types. We summarize here pathological data for animal models and macroscopic histological examination data from recent clinical records, which we link to the effects of toxins. We describe three major steps in infection: (i) an invasion phase in the lung, during which toxins have short-distance effects on lung phagocytes; (ii) a phase of bacillus proliferation in the mediastinal lymph nodes, with local effects of toxins; and (iii) a terminal, diffusion phase, characterized by a high blood bacterial load and by long-distance effects of toxins, leading to host death. The pathophysiology of inhalational anthrax thus involves interactions between toxins and various cell partners, throughout the course of infection.

[Anthrax revisited: Bacillus anthracis toxins as novel actors of immune escape?]. / La maladie du charbon revue: les toxines de Bacillus anthracis comme nouveaux acteurs de l'evasion immunitaire de l'agent pathogène?

The recent bioterrorist attacks have stressed the need of a better knowledge of Bacillus anthracis infection pathophysiology. We present here the increasing interests of B. anthracis studies in term of bio-defense, the main pathogen characteristics, the main clinical features of inhalational anthrax (the pulmonary form of the disease), and recent aspects of its physiopathology. Next, we address the main results concerning the toxin effects on immune system through impairing the dendritic cell functions, and we analyze the singular role of anthrax toxins in immune evasion.

Resident CD11c+ lung cells are impaired by anthrax toxins after spore infection.

Bacillus anthracis secretes 2 toxins: lethal toxin (LT) and edema toxin (ET). We investigated their role in the physiopathologic mechanisms of inhalational anthrax by evaluating murine lung dendritic cell (LDC) functions after infection with B. anthracis strains secreting LT, ET, or both or with a nontoxinogenic strain. Three lung cell populations gated on CD11c/CD11b expression were obtained after lung digestion: (1) CD11c(high)/CD11b(low) (alveolar macrophages), (2) CD11c(intermediate (int))/CD11b(int) (LDCs), and (3) CD11c(low)/CD11b(high) (interstitial macrophages or monocytes). After infection with LT-secreting strains, a decrease in costimulatory molecule expression on LDCs was observed. All CD11c+ cells infected with a nontoxinogenic strain secreted tumor necrosis factor (TNF)- alpha , interleukin (IL)-10, and IL-6. LT-secreting strains inhibited overall cytokine secretion, whereas the ET-secreting strain inhibited only TNF- alpha secretion and increased IL-6 secretion. Similar results were obtained after preincubation with purified toxins. Our results suggest that anthrax toxins secreted during infection impair LDC function and suppress the innate immune response.

Evidence for adjuvanticity of anthrax edema toxin.

Bacillus anthracis edema factor (EF) is an adenylate cyclase that increases intracellular cAMP concentrations. Since EF is present as a contaminant in the licensed protective antigen(PA)-based vaccines, we investigated its effect on anti-PA humoral immune response in BALB/c mice. We observed a significant increase of anti-PA IgG response in mice immunised with PA in association with EF as compared to PA alone. These results clearly show an adjuvant effect of EF, which is consistent with the data concerning the cellular effects of EF on antigen-presenting cells.

Anthrax edema toxin cooperates with lethal toxin to impair cytokine secretion during infection of dendritic cells.

Bacillus anthracis secretes two critical virulence factors, lethal toxin (LT) and edema toxin (ET). In this study, we show that murine bone marrow-derived dendritic cells (DC) infected with B. anthracis strains secreting ET exhibit a very different cytokine secretion pattern than DC infected with B. anthracis strains secreting LT, both toxins, or a nontoxinogenic strain. ET produced during infection selectively inhibits the production of IL-12p70 and TNF-alpha, whereas LT targets IL-10 and TNF-alpha production. To confirm the direct role of the toxins, we show that purified ET and LT similarly disrupt cytokine secretion by DC infected with a nontoxinogenic strain. These effects can be reversed by specific inhibitors of each toxin. Furthermore, ET inhibits in vivo IL-12p70 and IFN-gamma secretion induced by LPS. These results suggest that ET produced during infection impairs DC functions and cooperates with LT to suppress the innate immune response. This may represent a new strategy developed by B. anthracis to escape the host immune response.

Fever-like thermal conditions regulate the activation of maturing dendritic cells.

Fever is one of the most frequent clinical signs encountered in pathology, especially with respect to infectious diseases. It is currently thought that the role of fever on immunity is limited to activation of innate immunity; however, its relevance to activation of adaptive immunity remains unclear. Dendritic cells (DCs) that behave as sentinels of the immune system provide an important bridge between innate and adaptive immunity. To highlight the role of fever on adaptive immunity, we exposed murine bone marrow-derived lipopolysaccharide (LPS)- or live bacteria-maturing DCs over a 3-h period to 37 degrees C or to fever-like thermal conditions (39 degrees C or 40 degrees C). At these three temperatures, we measured the kinetics of cytokine production and the ability of DCs to induce an allogeneic mixed lymphocyte reaction. Our results show that short exposure of DCs to temperatures of 39 degrees C or 40 degrees C differentially increased the secretion of interleukin (IL)-12p70 and decreased the secretion of IL-10 and tumor necrosis factor alpha by maturing DCs. These fever-like conditions induced a regulation of cytokine production at the single-cell level. In addition, short-term exposed LPS-maturing DCs to 39 degrees C induced a stronger reaction with allogeneic CD4(+) T cells than maturing DCs incubated at 37 degrees C. These results provide evidence that temperature regulates cytokine secretion and DC functions, both of which are of particular importance in bacterial diseases.